Integrative Transcriptomics Identified Non-sarcomeric Dysregulated Ion Homeostasis and Innate Immunity genes as Therapeutic Targets in Hypertrophic Cardiomyopathy (HCM)

Background Hypertrophic Cardiomyopathy (HCM) is the most prevalent monogenic cardiac disease. Currently, there is no effective cure; management is strictly palliative and focused on symptom relief. Most of its known genetics are sarcomeric, but non-sarcomeric genetics remain poorly characterized. This study used transcriptomics, network biology, and target-based drug knowledge-mining to uncover non-sarcomeric pathological pathways and candidate drugs. Methods Human myocardial RNA-seq data were obtained from the NCBI Sequence Read Archive (Bioproject PRJNA961804). Raw reads were mapped to the human reference genome (GRCh38) using Bowtie2, and quantified with featureCounts. Differential expression was calculated using DESeq2 (|log2FC| ≥ 3, p -adj < 0.05). A protein-protein interaction (PPI) network was constructed by integrating STRING, BioGrid, OmniPath, InWeb_IM and analyzed in Cytoscape using MCODE and CytoHubba. Functional enrichment was done with ShinyGO and Enrichr. Drugs were retrieved from DrugBank for use as candidate drugs. Results 86 high-confidence differentially expressed genes (24 up-, 62 down-regulated) were identified. Two dysregulated pathways were found to converge with enrichment: mineral absorption (down-regulation of both metallothioneins MT1A and MT1M ) and neutrophil extracellular trap formation (down-regulation of both FPR1 and FPR2 ). Hub genes included FPR1, FPR2, CXCR1, CCR1, SSTR5, EDN2, EDN3, S100A8, S100A9, and TLR2 . Zinc-containing compounds and formyl-peptide-receptor antagonists (rebamipide, nedocromil) were found through target-based drug knowledge mining. Conclusion These results identify zinc homeostasis and innate immunity as potential non-sarcomeric pathways in HCM. Key caveats of this study include the small sample size, lack of protein level validation and predictive nature of the results of drug knowledge mining. The mechanisms proposed are hypothesis in need of experimental validation.